The overall objective of this research application is to focus on major vulnerability factors in drug abuse, including avidity for nondrug rewards, impulsive behavior, sex, and ovarian hormones, and determine how groups with differing vulnerability levels respond to treatment efforts. Both behavioral (nondrug alternatives) and pharmacological (medication) treatments will be examined. A main goal is also to study treatment approaches as they are applied during several key phases of addiction such as acquisition of initial drug use, escalation from controlled to uncontrolled drug abuse, and reinstatement of drug seeking (relapse) after a period of abstinence. These transition phases, and particularly reinstatement, are the greatest challenges to solving drug abuse problems. Much of the previous work has been conducted with cocaine (COC), and that work will be extended to new areas;however, new proposed studies will also be conducted with methamphetamine (METH), a drug that has become an enormous health concern and for which prevention and treatment models are urgently needed. The following are the Specific Aims that correspond to 5 proposed experiments: Aim 1, to examine sex and hormonal influences in drug abuse vulnerability, a) during vulnerable phases of drug abuse, specifically, acquisition, escalation, and reinstatement, and to examine the contributions of estrogen and progesterone to vulnerability status, b) to examine estrogen receptor sensitivity by comparing the contribution of agonists at the alpha and beta estrogen receptor subtypes with the goal of identifying more selective treatment targets, and c) by investigating the role of endogenous increases in progesterone that occur during pregnancy. Self-administration of COC and METH will be compared before, during, and after pregnancy and weaning to determine whether elevated levels of drug self-administration decrease when progesterone is elevated. Aim 2, to study the effects of behavioral interventions for reducing the escalation and reinstatement of COC and METH abuse in vulnerable groups. Behavioral interventions will be examined as a function of individual differences in vulnerability, such as male versus female, and those rated as high versus low on impulsivity, wheel-running, and sucrose intake. Aim 3, to explore the use of medications at vulnerable phases of drug abuse in vulnerable phenotypes. Medications to be tested will be baclofen, a gamma aminobutyric acid B (GABAB) agonist that blocks many aspects of drug abuse, and progesterone which has been shown to reduce drug-seeking behavior and the positive subjective effects of drugs in females and males, animals and humans. We currently have no viable treatments for COC, METH, or several other forms of stimulant abuse. The proposed research will show how enhanced drug-seeking behavior in vulnerable phenotypes can be reduced at the most critical, vulnerable phases of drug abuse through behavioral and pharmacological interventions.